摘要
肉桂酸属于多酚类酚酸,最丰富的植物次生代谢产物之一。因为它们的生物活性过多,所以这些物质被广泛地研究。特别是,它们有助于抑制蛋白激酶在细胞的多效性。蛋白激酶在调控细胞信号网络中很关键。致癌蛋白激酶的选择靶向性增加了临床抗癌功效。在过去三年中,肉桂酸及相关化合物激发了研究人员在众多的合成和半合成的致癌蛋白激酶抑制剂的设计。近年来,在肉桂支架化合物方面的兴趣复苏,这是由现代药物设计和发现的方法刺激而来,如在体外和在硅片高温超导。本文综述了肉桂酸衍生物和类似物对蛋白激酶的直接抑制作用的鉴定。我们也总结上述蛋白激酶家族验证的意义,或有前途的抗癌疗法的目标。抑制方式可能会有所不同从竞争性三磷酸腺苷,通过双底物竞争和混合竞争,到非竞争性三磷酸腺苷。激酶的选择性往往是微妙的化学修饰相关的,也可以通过一个额外的非肉桂片段的抑制控制。具体的肉桂酸同系物可能在细胞的多种活动有协同作用,如额外的酶抑制,例如去泛素化酶影响相同的信号通路(如JAK2/STAT)。由于肉桂酸其生物和物理化学性质,提供由自然启发的能导致新的致癌蛋白激酶抑制剂的和相关的酶的想法,这能够针对各种癌细胞。
关键词: 抗肿瘤,融合蛋白,肉桂酸,酯姜黄素,CK2,姜黄素,表皮生长因子受体,人类表皮生长因子受体II,JAK2,激酶,雷帕霉素靶蛋白信号传导与转录激活子,PIM1
Current Medicinal Chemistry
Title:Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases – Structure, Mechanisms and Biomedical Effects#
Volume: 23 Issue: 10
Author(s): Marcin Mielecki, Bogdan Lesyng
Affiliation:
关键词: 抗肿瘤,融合蛋白,肉桂酸,酯姜黄素,CK2,姜黄素,表皮生长因子受体,人类表皮生长因子受体II,JAK2,激酶,雷帕霉素靶蛋白信号传导与转录激活子,PIM1
摘要: Cinnamic acid belongs to phenolic-acid class of polyphenols, one of the most abundant plant secondary metabolites. These substances are widely studied because of plethora of their biological activities. In particular, their inhibition of protein kinases contributes to the pleiotropic effects in the cell. Protein kinases are essential in controlling cell signaling networks. Selective targeting of oncogenic protein kinases increases clinical anticancer efficacy. Cinnamic acid and related compounds have inspired researchers in the design of numerous synthetic and semisynthetic inhibitors of oncogenic protein kinases for the past three decades. Interest in cinnamoyl-scaffold-containing compounds revived in recent years, which was stimulated by modern drug design and discovery methodologies such as in vitro and in silico HTS. This review presents cinnamic acid derivatives and analogs for which direct inhibition of protein kinases was identified. We also summarize significance of the above protein kinase families – validated or promising targets for anticancer therapies. The inhibition mode may vary from ATP-competitive, through bisubstrate-competitive and mixedcompetitive, to non-competitive one. Kinase selectivity is often correlated with subtle chemical modifications, and may also be steered by an additional non-cinnamoyl fragment of the inhibitor. Specific cinnamic acid congeners may synergize their effects in the cell by a wider range of activities, like suppression of additional enzymes, e.g. deubiquitinases, influencing the same signaling pathways (e.g. JAK2/STAT). Cinnamic acid, due to its biological and physicochemical properties, provides nature-inspired ideas leading to novel inhibitors of oncogenic protein kinases and related enzymes, capable to target a variety of cancer cells.
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Cite this article as:
Marcin Mielecki, Bogdan Lesyng , Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases – Structure, Mechanisms and Biomedical Effects#, Current Medicinal Chemistry 2016; 23 (10) . https://dx.doi.org/10.2174/0929867323666160316123609
DOI https://dx.doi.org/10.2174/0929867323666160316123609 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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